Aminopeptidase P inhibitors and uses thereof

Abstract

The present invention is directed to a compound of the formula: ##STR1## or a pharmaceutically acceptable addition salt thereof, wherein C 3 and C 2 in combination have the configuration S,R or R,S; wherein Y is straight or branched chain lower alkyl having 1 to 6 carbon atoms, straight or branched chain lower alkenyl or alkynyl having 2-6 carbon atoms, cyclic alkyl or alkenyl having 5 or 6 carbon atoms, or benzyl; and wherein X is an amino acid or an oligopeptide having from 1 to 8 amino acid residues, the first amino acid residue at the N-terminus of X being a natural or a synthetic L-amino acid having a radius of gyration of less than 1.54 Å, X also having a carboxyl or a carboxyamide moiety at its carboxy terminus. The present invention is further directed to a pharmaceutical composition and to a method of inhibiting bradykinin degradation in a patient using the above-described compound.

I claim: 
     
       1. A compound of the formula: ##STR9## or a pharmaceutically acceptable addition salt thereof, wherein C 3  and C 2  in combination have the configuration S,R or R,S; wherein Y is straight or branched chain lower alkyl having 1 to 6 carbon atoms, straight or branched chain lower alkenyl or alkynyl having 2-6 carbon atoms, cyclic alkyl or alkenyl having 5 or 6 carbon atoms, or benzyl; and   wherein X is an amino acid or an oligopeptide having from 1 to 8 amino acid residues, the first amino acid residue at the N-terminus of X being a natural or a synthetic L-amino acid with a radius of gyration of less than 1.54 Å, X also having a carboxyl or a carboxyamide moiety at its carboxy terminus.   
     
     
       2. The compound of claim 1 wherein X is an oligopeptide having 2 amino acid residues. 
     
     
       3. The compound of claim 2 wherein X is -Pro-Ala-NH 2  and Y is a member selected from the group consisting of isobutyl and benzyl. 
     
     
       4. The compound of claim 1 wherein said pharmaceutically acceptable addition salt is a member selected from the group consisting of the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetete, propionate, lactate, meleate, malate, succinate and tartrate. 
     
     
       5. The compound of claim 4 wherein said addition salt is acetate. 
     
     
       6. The compound of claim 4 wherein said addition salt is sulfate. 
     
     
       7. A pharmaceutical composition comprising: ##STR10## or a pharmaceutically acceptable addition salt thereof, wherein C 3  and C 2  in combination have the configuration S,R or R,S; wherein Y is straight or branched chain lower alkyl having 1 to 6 carbon atoms, straight or branched chain lower alkenyl or alkynyl having 2-6 carbon atoms, cyclic alkyl or alkenyl having 5 or 6 carbon atoms, or benzyl; and   wherein X is an amino acid or an oligopeptide having from 1 to 8 amino acid residues, the first amino acid residue at the N-terminus of X being a natural or a synthetic L-amino acid having a radius of gyration of less than 1.54 Å, X also having a carboxyl or a carboxyamide moiety at its carboxy terminus.   
     
     
       8. The pharmaceutical composition of claim 7 wherein X has 2 amino acid residues. 
     
     
       9. The pharmaceutical composition of claim 8 wherein X is -Pro-Ala-HN 2 . 
     
     
       10. The pharmaceutical composition of claim 9 wherein said pharmaceutically acceptable addition salt is a member selected from the group consisting of the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, realate, succinate, and tartrate. 
     
     
       11. The pharmaceutical composition of claim 10 in unit dosage form. 
     
     
       12. The pharmaceutical composition of claim 11 wherein said pharmaceutically acceptable carrier is a pharmaceutically acceptable fluid suitable for intravenous infusion. 
     
     
       13. The pharmaceutical composition of claim 10 wherein said pharmaceutically acceptable addition salt is sulfate. 
     
     
       14. The pharmaceutical composition of claim 10 wherein said pharmaceutically acceptable addition salt is acetate. 
     
     
       15. The pharmaceutical composition of claim 10 wherein Y is isobutyl. 
     
     
       16. The pharmaceutical composition of claim 10 wherein Y is benzyl. 
     
     
       17. A method of inhibiting bradykinin degradation in a mammalian patient comprising: administering to a mammalian patient in need of inhibition of bradykinin degradation,   a therapeutically effective amount of a compound of the formula: ##STR11## or a pharmaceutically acceptable addition salt thereof, wherein C 3  and C 2  in combination have the configuration S,R or R,S;   wherein Y is straight or branched chain lower alkyl having 1 to 6 carbon atoms, straight or branched chain lower alkenyl or alkynyl having 2-6 carbon atoms, cyclic alkyl or alkenyl having 5 or 6 carbon atoms, or benzyl; and   wherein X is an amino acid or an oligopeptide having from 1 to 8 amino acid residues, the first amino acid residue at the N-terminus of X being a natural or a synthetic L-amino acid having a radius of gyration of less than 1.54 Å, X also having a carboxyl or a carboxyamide moiety at its carboxy terminus.   
     
     
       18. The method of claim 17 wherein said mammalian patient is a human. 
     
     
       19. The method of claim 18 wherein said oligopeptide has two amino acid residues. 
     
     
       20. The method of claim 19 wherein X is the oligopeptide -Pro-Ala-NH 2 . 
     
     
       21. The method of claim 18 wherein said pharmaceutically acceptable addition salt comprises a member selected from the group consisting of the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, matate, succinate, and tartrate. 
     
     
       22. The method of claim 21 wherein said pharmaceutically acceptable addition salt is sulfate. 
     
     
       23. The method of claim 21 wherein said pharmaceutically acceptable addition salt is acetate. 
     
     
       24. The method of claim 17 further comprising the step of coadministering a therapeutically effective amount of an inhibitor to angiotensin converting enzyme. 
     
     
       25. The method of claim 24 wherein said compound and said inhibitor of angiotensin converting enzyme are administered to said patient by mouth. 
     
     
       26. The method of claim 24 wherein said compound and said inhibitor of angiotensin converting enzyme are administered parenterally to said patient. 
     
     
       27. The method of claim 24 wherein said inhibitor of angiotensin convening enzyme is a member selected from the group consisting of captopril, enalapril, enalaprilat, lisinopril, quinapril, benazepril, fosinopril, ramipril, and ramiprilat. 
     
     
       28. The method of claim 27 wherein said inhibitor of angiotensin convening enzyme is captopril. 
     
     
       29. The method of claim 27 wherein said inhibitor of angiotensin converting enzyme is enalapril. 
     
     
       30. The method of claim 27 wherein said inhibitor of angiotensin converting enzyme is enalaprilat. 
     
     
       31. The method of claim 27 wherein said inhibitor of angiotensin converting enzyme is lisinopril. 
     
     
       32. The method of claim 23 wherein said inhibitor of angiotensin converting enzyme is a member of the group consisting of ramipril and ramiprilat.